Aspirin-exacerbated respiratory disease (AERD) is a severe disorder characterized by asthma, recurrent nasal polyposis, and marked eosinophilic inflammation of the sinonasal and bronchial mucosa. It accounts for ~5% of asthma, and for a disproportionate share (~30%) of severe asthma. Therapeutic options are limited by a lack of understanding of disease pathogenesis. No suitable animal model has been reported to date. This proposal uses a novel mouse model of AERD to test the overriding hypothesis that AERD arises in hosts who are predisposed to abnormal function of any one of several interconnected control points of a lipid mediator hierarchy. These abnormalities result in failure of the prostaglandin (PG)E2-EP2 receptor system to control the synthesis and effector actions of cysteinyl leukotrienes (cys-LTs). A superimposed inflammatory insult results in markedly exaggerated eosinophilic respiratory tract inflammation with augmented downstream pathogenetic effects of the thromboxane A2 (TXA2)-T prostanoid (TP) receptor system as a final common pathway. We have found that house dust mite-treated ptges-/- mice (which lack the capacity to produce PGE2 through the inducible COX-2 enzyme), but not WT controls, bronchoconstrict when challenged by inhalation with inhaled lysine-aspirin (Lys-ASA), and generate ~3-fold higher quantities of cys-LTs than do WT controls. Remarkably, genetic deletion or pharmacologic blockade of TP receptors completely protect ptges-/- mice from bronchial eosinophilia, Th2 cytokine generation, and pulmonary ICAM-1 induction despite persistent high level pulmonary cys-LT production. We now seek to determine precisely how perturbations at individual control points in a lipid mediator hierarchy lead to the phenotype of AERD. Because our data suggest that TP receptors may be major therapeutic targets in AERD, we will also seek to identify the mechanism(s) that account for their functions. The studies proposed will reveal potential causative mechanisms in AERD and identify therapeutic targets that could restore normal homeostasis.